1. Technical Field of the Invention
The present invention relates to methodology and microfluidic apparatus/device for monitoring the crystallization of a substance and to a screening protocol comprising such methodology.
This invention more particularly features, but not exclusively, the study of polymorphism, namely, the possibility that a given molecule crystallizes in different crystalline structures without however changing chemical composition. The various crystalline forms that can be adopted by this molecule are called polymorphs.
2. Description of Background and/or Related and/or Prior Art:
The fact of predicting which polymorph is likely to crystallize is of great importance in chemical and pharmaceutical processes, insofar as each polymorph of a given substance has specific physical properties. Compare the following publications: J. Bernstein, J. Phys. D. Appl. Phys., 26, 66 (1993); K. Sato, J. Phys. D. Appl. Phys., 26, 77 (1993); and J. Bernstein, J. Davey and J. O. Henck, Angew. Chem. Int. Ed., 88, 3440 (1999).
However, complete understanding of the complexity of the process of crystallization in solution is lacking from the prior art. Such a lack is in particular due to existing links from the thermodynamic characteristics of phase diagrams and the kinetics of phase transitions (particularly nucleation), to the experimental difficulties in obtaining reliable and reproducible measurements, because of the presence of impurities, and to the large number of parameters, such as the pH, the temperature or the presence of solvent, which play an important role. To illustrate the latter point, see the following publications: J. W. Mullin, Crystallisation (Butterworth-Heinemann, Oxford, 2001); A. C. Zettlemoyer, Nucleation (Marcel Dekker, New York, 1969); N. Rodriguez-Hornedo and D. Murphy, Journal of Pharmaceutical Sciences 88, 651 (1999); D. Kashchiev, D. Clausse and C. Jolivet-Dalmazzone, J. Colloid Interface Sci., 165, 148 (1994).
High-flow-rate techniques are likely to improve this understanding, by providing the possibility of greater screening of the crystallization conditions. In addition, microfluidics appears to be a good gateway for such experiments, insofar as it offers very precise control, through the design of specific kinetic pathways in phase diagrams. With regard to the latter aspect, refer to the following publications: C. L. Hansen, S. Classen, J. M. Berger and S. R. Quake, J. Am. Chem. Soc., 128, 3142 (2006); J. Leng, B. Lonetti, P. Tabeling, M. Joanicot and A. Ajdari, Phys. Rev. Lett., 96, 084503 (2006); C. J. Gerdts, V. Tereshko, M. K. Yadav, I. Dementieva, F. Collart, A. Joachimiak, R. C. Stevens, P. Kuhn, A. Kossiakoff and R. F. Ismagilov, Angew. Chem. Int. Ed. Engl., 45, 8156 (2006).
In addition, microfluidics offer the possibility of screening a very large number of physico-chemical systems using very small amounts of compounds, typically varying from the range of nanoliters (nl) to microliters (μl). With regard to the latter point, namely the “Lab on chip” technology, also compare the following publications: C. L. Hansen, E. Skordalakee, J. M. Berger and S. R. Quake, Proc. Natl. Acad. Sci., USA 99, 16531 (2002); D. L. Chen and R. F. Ismagilov, Current Opinion in Chemical Biology, 10, 226 (2006); K. Shinohara, T. Fukui, H. Abe, N. Sekimura and K. Okamoto, Langmuir 22, 6477 (2006); B. Zheng, J. D. Tica, L. S. Roach and R. F. Ismagilov, Angew. Chem. Int. Ed., 43, 2508 (2004).